Epidemiological studies have shown that shift work is associated with an increased risk for the development of diabetes, obesity, and cardiovascular disease. Recent animal studies and acute human studies suggest that this association may be due to the misalignment between the fasting/feeding and sleep/wake cycles relative to the cycle of the endogenous circadian timing system. That is, activity and food intake during the 'biological night' or sleep loss during the 'biological day' may result in metabolic, autonomic and endocrine changes that pre-dispose to diabetes, obesity, and cardiovascular disease. For instance, we recently found that acute experimental misalignment between the sleep/wake and fasting/feeding cycle-typical of shift work-can lead to significantly decreased plasma leptin, increased plasma glucose and increased mean arterial pressure. We also found reduced sleep efficiency during circadian misalignment to an extent that has been shown to significantly decrease circulating leptin, increase appetite and increase sympatho-vagal balance in other acute studies. Building on these new findings, and overcoming a number of limitations in the prior work, we aim to determine the progressive physiological changes across a work week of realistic simulated shift work focusing on those metabolic, endocrine, inflammatory, and cardiovascular variables that are biomarkers of susceptibility to the development of diabetes, obesity, and cardiovascular disease. Also, since the effect of shift work is most clinically relevant in actual shift workers, we will determine whether the potential maladaptive physiological effects are observed also in chronic shift workers or that this population has adapted. We will use a 14 day/night laboratory protocol involving a within-subject, randomized, cross-over design including a simulated night shift and day shift schedule using a formal battery of scheduled behaviors and light exposures in healthy day workers and shift workers. The principal dependent variables are derived from circulating adipocyte hormones (leptin, adiponectin, resistin, ghrelin), measures of insulin resistance (mixed meal response and intravenous glucose tolerance test), inflammatory markers (CRP, IL-6, TNF-alpha, MCP-1), peripheral vascular endothelial function, and autonomic control (catecholamines, sympatho-vagal balance, baroreceptor sensitivity and systemic blood pressure). Changes in these variables will be monitored across numerous days and nights of shift work, compared between day and night shift schedules, and compared between non-shift workers and chronic shift workers. Following on from the convincing epidemiological studies and recent acute physiology studies, the proposed intense physiological study utilizing realistic shift work-schedules over a number of days are now needed to determine the specific underlying metabolic, endocrine, inflammatory, autonomic and cardiovascular mechanisms that explain the adverse health consequences of chronic shift work. We anticipate that this work will lay the groundwork for the development of targeted and timed therapies to counteract the public health burden of shift work.